A Cost-Benefit Analysis of Lipid Standardization in the United States

Introduction By improving lipid standardization, the Centers for Disease Control and Prevention's (CDC's) Lipid Standardization Program and Cholesterol Reference Method Laboratory Network have contributed to the marked reduction in heart disease deaths since 1980. The objective of this study was to estimate the benefits (ie, the value of reductions in heart disease deaths) and costs attributable to these lipid standardization programs. Methods We developed a logic model that shows how the inputs and activities of the lipid standardization programs produce short- and medium-term outcomes that in turn lead to improvements in rates of cardiovascular disease and death. To calculate improvements in long-term outcomes, we applied previous estimates of the change in heart disease deaths between 1980 and 2000 that was attributable to statin treatment and to the reduction in total cholesterol during the period. Experts estimated the share of cholesterol reduction that could be attributed to lipid standardization. We applied alternative assumptions about the value of a life-year saved to estimate the value of life-years saved attributable to the programs. Results Assuming that 5% of the cholesterol-related benefits were attributable to the programs and a $113,000 value per life-year, the annual benefit attributable to the programs was $7.6 billion. With more conservative assumptions (0.5% of cholesterol-related benefits attributable to the programs and a $50,000 value per life-year), the benefit attributable to the programs was $338 million. In 2007, the CDC lipid standardization programs cost $1.7 million. Conclusion Our estimates suggest that the benefits of CDC's lipid standardization programs greatly exceed their costs.


Introduction
Cholesterol awareness and control are important factors in reducing deaths from heart disease in the United States and are a key focus of health promotion and clinical practice (1). Age-adjusted death rates for heart disease have dropped in the United States from 1980 (412.1 per 100,000 population) to 2000 (257.6 per 100,000 population) and 2006 (200.2 per 100,000 population) (2,3). Using a model of the impact of various risk factors and treatments on heart disease deaths, Ford et al (4) and Capewell et al (5) attributed nearly one-third of the reduction in heart disease deaths between 1980 and 2000 to a reduction in the prevalence of high cholesterol and improved secondary prevention using statin drugs to control cholesterol in people with previous heart disease.
An important but sometimes overlooked contribution to improvements in cholesterol awareness and control has been provided by the Centers for Disease Control and Prevention's (CDC's) Lipid Standardization Program (LSP) and Cholesterol Reference Method Laboratory Network (CRMLN) ("lipid standardization programs" hereafter). The LSP is an accuracy-based program that defines benchmark reference methods and maintains stable pools of reference testing materials (6,7). Its standardization activities have supported epidemiologic studies that identified the role of cholesterol in heart disease and clinical research laboratories that conducted standardized clinical trials to test the effects of alternative treatments to reduce cholesterol. The CRMLN is a network of laboratories replicating the CDC reference methods to help manufacturers improve the accuracy of clinical testing methods (8).
Because only a few manufacturers produce the diagnostic equipment and supplies used in cholesterol testing, facilitating accurate manufacturer calibration results in more accurate clinical testing nationwide (9).
As a cost-saving measure, in 2008 the National Heart, Lung, and Blood Institute (NHLBI) retracted its 50year budgetary commitment to the LSP. Without the NHLBI funding, the LSP and CRMLN programs may not be able to continue in their present form. In response, the Cardiovascular Biomarker Standardization Steering Committee of the National Association of Chronic Disease Directors (NACDD) asked NACDD to conduct a cost-benefit study of the LSP. The objective of this study was to estimate the benefits and costs of the LSP and CRMLN.
Results of the study may be used by policy makers to determine the value of lipid standardization.

Logic model development
We first developed a logic model for assessing the impact of the CDC lipid standardization programs ( Figure 1). Logic models are a program evaluation tool used to graphically depict major elements and causality pathways of a program (10). The left side of the logic model lists the resources (inputs) necessary for program operation. The logic model then shows the major program activities; the participants involved with and affected by these activities; and the short-, medium-, and long-term outcomes of the programs.
The programs are currently supported by CDC and previously were jointly funded by NHLBI. We do not consider participation costs incurred by clinical laboratories, manufacturers, and research funding agents because participation in the programs is voluntary.
The fundamental activities of the programs are to define reference methods and maintain reference materials for total cholesterol, high-density lipoprotein cholesterol, lowdensity lipoprotein (LDL) cholesterol, and triglycerides. CDC uses a standardized testing protocol on well-characterized and uniform serum materials to eliminate potential reference bias and allow program participant results to be compared directly to the CDC reference results. The programs maintain a set of frozen serum pools that exhibit a wide range of lipid concentrations. Long-term maintenance of these pools is essential to ensure that reference values of these samples do not drift over time.
Using the reference measurement procedures and materials, the LSP conducts standardization of clinical laboratories involved in epidemiologic and clinical research. Establishing a long-term, accuracy-based reference allows results to be compared across different laboratories and over time, which is necessary when conducting multicenter clinical trials; comparing lipid measurement values to past values, such as the baseline period in clinical and epidemiologic research; or comparing lipid measurement values across clinical and epidemiologic research studies. Recommended accuracy goals for lipids and lipoprotein tests, which include both bias and imprecision, have been developed by the National Cholesterol Education Program (11)(12)(13). These accuracy goals are based on results obtained from the LSP.
The CRMLN uses the standardized reference methods and materials to certify a network of reference laboratories that seek to replicate the accuracy of the CDC laboratory. In turn, this network of laboratories certifies participat- The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.
ing manufacturers and clinical testing laboratories. By calibrating manufacturers' equipment and testing methods against the CDC reference standards, the CRMLN increases the accuracy of all tests conducted using these supplies, even for clinical laboratories that do not participate in the program. This system allows for accurate comparison of test results to the clinical practice guidelines established by the Adult Treatment Panel III (14).
The programs' inputs, activities, and participants are intended to produce the following short-term outcomes: • Standardized epidemiologic results, which lead to improved treatment recommendations. • Standardized clinical trials, which lead to improved comparisons of alternative treatments. • Standardized routine testing methods, which lead to the improved cholesterol test accuracy necessary for improved diagnosis.
The short-term outcomes -in combination with nonprogram factors -lead to the following medium-term outcomes for patients and health care providers: increased cholesterol awareness, better practice patterns, improved diet and exercise, better drugs, and improved diagnosis of patients with high cholesterol.
The medium-term outcomes combine to produce better cholesterol control, which improves patient health outcomes in the long term by reducing medical events and lowering rates of cardiovascular disease and death. The true benefits of the lipid standardization programs arise from improvements in these long-term patient outcomes.

Quantifying outcomes
It is difficult to quantify precisely the effect of the lipid standardization programs on these short-, medium-, and long-term outcomes. For most of the outcomes, standardization of lipid measures is a prerequisite that can support and promote -but does not by itself guarantee -improved public health outcomes. For example, standardization supports clinical trials of new cholesterol-lowering therapies, but development of new therapies also depends on research and development efforts, technologic breakthroughs, and careful clinical testing.
Because we cannot directly attribute outcome changes to program operations, our approach is to investigate improvements in each short-and medium-term outcome during recent years. We discuss qualitatively how the standardization efforts of CDC programs may have facilitated the improvement, but we do not attempt to estimate precisely the share of each improvement that is attributable to the programs. We also do not place a dollar value on the benefits of improvements in short-and mediumterm outcomes because the true benefits to patients are associated with improvements in long-term outcomes.
To determine the improvements in long-term outcomes, we applied previous estimates of the change in heart disease deaths between 1980 and 2000 that was attributable to treatment with statins and the overall reduction in total cholesterol during the period. Ford et al (4) and Capewell et al (5) estimated that these cholesterol-related changes prevented or postponed more than 111,000 deaths and saved 1.35 million life-years in 2000 (Table 1).
We considered alternative assumptions about the share of deaths prevented or postponed and life-years saved that were attributable to the lipid standardization programs.
We asked experts to estimate the percentage of lipid reduction during the period that was attributable to the lipid standardization programs. The 4 experts work on cardiovascular disease in various settings (1 in a university hospital, 2 in private clinical laboratories, and 1 in the National Institutes of Health). The experts were asked to base their estimates on information on the reduction in CHD deaths between 1980 and 2000 and the estimate (4) that 24% of the reduction was due to lower cholesterol levels. They were told that lipid standardization was potentially one of many factors contributing to lower lipid levels. The experts' median estimate of the share of lipid reduction attributable to lipid standardization was 5%, but the estimates ranged widely (from 2%-3% to >50%). We also considered more conservative estimates of 0.5% and 1%.

Results
As detailed in the Appendix, we found suggestive evidence linking the LSP and CRMLN to improved short-and medium-term outcomes. Program data indicate that laboratories participating in the programs achieve high levels of accuracy. This accuracy supports standardized epidemiologic results, standardized clinical trials, and standardized testing methods used by clinical laboratories, which can lead to improved test accuracy.
Assuming the median expert panel estimate of 5% of the cholesterol-related benefits attributable to the programs and a value per life-year of $113,000, the benefits attributable to the programs are estimated to be $7.6 billion ( Table  2). Assuming the most conservative estimates (0.5% of the cholesterol-related benefits attributable to the programs and a $50,000 value per life-year), the benefits attributable to the programs are estimated to be $338 million annually.
We conducted a sensitivity analysis to examine how the estimated benefits change under alternative assumptions about the percentage attributable to the LSP and CRMLN ( Figure 2) in comparison to this cost. Both the percentage attributable and the benefits and costs are presented using logarithmic scales to preserve the true linear relationship between the benefit and the percentage attributable and to allow the benefits and costs to be shown in the same figure (otherwise, the benefit at 5% attributable would completely dwarf the cost of the programs). Even assuming that the LSP and CRMLN are responsible for only 0.01% of the improvement in life-years attributable to cholesterol-related factors, the benefits of the programs substantially exceed their costs.

Discussion
Our estimates suggest that the benefits of CDC's lipid standardization programs greatly exceed their costs. Deaths from heart disease fell dramatically between 1980 and 2000 (2,3), and this reduction has driven improvements in overall life expectancy. The improvement in life-years has high dollar value. A significant share of the improvement in heart disease deaths is due to cholesterol-related factors, including the overall reduction in total and LDL cholesterol and the use of statin drugs for secondary and primary prevention (4,5). To the extent that some of the improvement in these cholesterol-related factors is due to CDC's lipid standardization programs, the programs have large dollar benefits because the overall dollar value of the increase in life-years from heart disease -and the share of the increase that is attributable to cholesterol-related factors -is so large. Put another way, the overall benefits of cholesterol reduction are so large that there is plenty of credit to go around to lipid standardization programs and other factors (eg, research and development efforts, technological breakthroughs, careful clinical testing) affecting cholesterol. Even if the LSP and CRMLN receive only a small share of the credit, the programs' benefits exceed their costs. Our analysis has several potential limitations. First, our estimates could implicitly overestimate the value of the improvements in life expectancy stemming from reductions in heart disease deaths; however, this does not appear to be the case. Improvements in heart disease deaths are clearly documented in national life expectancy and cause-of-death data. Less evidence exists on the value of this improvement, but a study by Murphy and Topel (18) provides context for our estimates. They estimated that the reduction in deaths from heart disease has increased the value of life by about $1.5 trillion per year since 1970. The Capewell et al study (5) -which is the basis for our estimates -found that 3.15 million life-years were gained in 2000 from all reductions in heart disease deaths between 1980 and 2000. When this gain is valued at $50,000, $113,000, and $300,000 per life-year, the total benefits in 2000 would be $155 billion, $350 billion, and $930 billion, respectively. Thus, the overall benefit from reduction in heart disease deaths given by Murphy and Topel is even greater than the underlying heart disease benefit in our analysis.
Second, our analysis could attribute too much of the gain in life-years resulting from reductions in heart disease deaths to cholesterol-related factors. We relied on studies by Ford et al (4) and Capewell et al (5), which appear to provide the most comprehensive decomposition of the gain in life-years that are attributable to specific factors.
Third, our estimate depends on the share of lipid reduction that is attributable to the lipid standardization programs, and this parameter was not precisely measured. Although the parameter was based on the opinion of experts familiar with the programs, these experts noted that the parameter was difficult to estimate. Even when we included more conservative parameters, the benefits attributable to the programs were still sizeable. Because this is probably the most important potential limitation of our study, it is worth considering additional alternative estimates.

Short-Term Outcomes: Improvements in Laboratory Standardization for Cholesterol Testing
The immediate outcome of improved lab standardization and manufacturer certification is an increase in the accuracy of cholesterol testing. The intention of the CDC lipid standardization programs is to improve the accuracy and comparability of research-related testing, primarily through the Lipid Standardization Program (LSP), and to improve the accuracy of general clinical tests directly through the Cholesterol Reference Method Laboratory Network (CRMLN). There is strong evidence that laboratory performance on cholesterol testing has improved through standardization during the past 25 years, although it is difficult to say how much of the improvement has been due to the LSP and CRMLN.

Accuracy of LSP Standardized Laboratories
The goal of the LSP is to ensure that member labs exhibit consistent accuracy in lipid testing over time. Early lipid testing was subject to significant levels of error and bias, so initial efforts of the LSP focused on improving the accuracy of lipid testing through the development and establishment of reference testing methods. As standardization was achieved, the LSP focus turned to maintaining accuracy of lipid testing. and no surveys yielded a CV of more than 3%. Note that the low number of observations may preclude drawing significant conclusions on the trend of "failing" labs over time.

Accuracy of Labs in CRMLN Clinical Laboratory Certification Program
Although the LSP results demonstrate that standardization is being achieved among the limited number of research-oriented LSP standardized labs, the primary mechanism through which the CDC laboratory standardization programs may increase clinical testing accuracy is through the CRMLN. The CRMLN labs are intended to replicate CDC reference methods to extend the reach of standardization, most importantly through the manufacturer certification process. The manufacturer certification process allows manufacturers to calibrate their equipment and supplies against accuracy-based reference values. When used by clinical testing labs, the calibrated supplies will presumably increase the accuracy of clinical testing conducted by these labs. A resource for evaluating how well this program works is to look at data from clinical laboratories that participate in the CRMLN's Clinical Laboratory Certification Program.

CAP Survey Results Show Improvement in Clinical Labs
Although the above tables show that standardization is being achieved among labs participating in the LSP and CRMLN, these results do not directly reflect the accuracy of the many nonprogram labs that conduct patient clinical testing. Table 3-3 shows the results of CAP proficiency testing surveys for total cholesterol for major methods/instruments peer groups between

3.2.b Subset of Labs that Passed Certification
Year 0bservations suggest that almost all participating laboratories meet current NCEP standards for total cholesterol (total error within 9% of the target level). Most participating laboratories meet National Cholesterol Education Program (NCEP) standards for HDL cholesterol (total error within 13% of the target level), although the performance is not as strong as on total cholesterol. The ABL should be useful for identifying trends in laboratory accuracy as more years of data become available.

Medium-Term Outcomes
Increasing the accuracy of research and clinical testing will result in several medium-term outcomes, including improving clinical diagnosis rates and   The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.
improving cholesterol-related research. Standardization of research testing has facilitated several important events, from the early research linking elevated total and LDL cholesterol to higher mortality, to more focused, clinical research on the efficacy of treatment and prevention interventions, including drugs and diet and exercise changes. Together, these findings have allowed for the creation of the ATP practice guidelines and provided the impetus for numerous public health campaigns targeted toward increasing physician and public awareness of the risks of high cholesterol and its modifiable risk factors.

Improved Clinical Diagnosis Rates
Better laboratory accuracy facilitates better diagnosis of persons with high cholesterol. If a laboratory produces biased cholesterol readings, some patients who truly need cholesterol reduction may not receive treatment, whereas other patients who do not need treatment may receive it. We used the data on bias from the method/instrument observations underlying Table  3-3 to estimate the percentage of patients whose total cholesterol would be misclassified in 2000 and 2006. We examined the ATP III cutoffs of 200   If we conduct this same exercise using the 1985 and 2009 CAP proficiency testing survey data, the share of the population that would be misclassified is much larger (Tables 3-8 and 3 -9) in 1985 with misclassifications falling dramatically by 2009. These results should be interpreted cautiously, however, because these specimens may have included matrix effects that distorted the true bias in patient samples.

Cholesterol Awareness
An important goal of public health programs focused on cholesterol is to increase awareness of the risks of high cholesterol among physicians and the general public. NCEP has focused efforts in two key areas: (1)  As with the development of the clinical guidelines, public health information campaigns are ultimately the product of multiple and disparate sources of data on the risks of high cholesterol and the effectiveness of different treatment and prevention strategies; as with the formation of the practice guidelines, this is possible only when the data used are directly comparable due to the underlying accuracy of the cholesterol measurements. Thus, the CDC lipid standardization programs have played an important role in facilitating the research necessary to inform, guide, and bolster public health information efforts.

Cholesterol-Lowering Drugs
There have been clear improvements in drug therapies to reduce LDL cholesterol levels and/or increase HDL cholesterol levels in recent years (the LSP does not standardize LDL testing, although the CRMLN does; to estimate LDL levels, most U.S. laboratories use the Friedewald equation, which depends on total cholesterol, HDL cholesterol, and triglyceride measures that are standardized by both programs). In particular, the introduction and The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.
widespread adoption of statins has revolutionized cholesterol management. Currently, six statins (atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin) are approved for use in the United States. These statins have been shown to reduce LDL cholesterol by 3% to 55%, with the most recently approved statins producing the largest reductions (Senior Journal, 2005). Other cholesterol-lowering drugs include ezetimide, nictonic acid, fenofibrate, and gemfibrozil.
The standardization of cholesterol measurement has played an important but difficult-to-quantify role in the development of cholesterol-lowering drugs. Cholesterol-lowering drugs are approved based primarily on their safety and their efficacy in lowering LDL cholesterol levels. To assess efficacy, it is necessary to accurately and reliably measure cholesterol levels. Standardization of cholesterol testing allows a large number of patients to be tested in large, multicenter clinical trials. Standardization also facilitates comparisons across trials and allows improvements in cholesterol to be assessed in the context of previous epidemiological studies showing the relationship between standardized cholesterol levels and clinical outcomes.

Diet and Exercise
In addition to pharmacological cholesterol reduction treatment, diet and exercise are important for ensuring reductions in cholesterol levels. On the basis of observational study findings, ATP III lists physical inactivity and an atherogenic diet (which generally includes high cholesterol) as major modifiable risk factors for high levels of LDL cholesterol and low levels of HDL cholesterol. The consumption of saturated fats and cholesterol has been falling since the early 1970s. In 1972, the average American consumed 355mg of cholesterol and 13.2g of saturated fat with a total energy intake of 1,983 kilocalories per day. By 1990, the cholesterol and fat intake measures had improved to 291mg of cholesterol and 12.6g of saturated fat with 2,199 kilocalories consumed per day (Ernst, Sempos, & Briefel, 1997). So while total caloric intake has markedly increased, cholesterol and saturated fat have decreased both in proportional and absolute levels. In the following decade, the proportion of calories from saturated fat continued to fall, although total cholesterol intake decreased only in men and actually increased by 11g per day in women (Carroll, Lacher, & Sorlie, 2005). However, the consumption of LDL cholesterol has decreased (Carroll, Lacher, & Sorlie, 2005). As with cholesterol medications, the evidence for the efficacy of lifestyle interventions to mitigate these risk factors came from clinical and epidemiological research, which, in most cases, benefited from increased accuracy due to the LSP.